ORIGINAL ARTICLE SMOKING Differences in regional air trapping in current smokers with normal spirometry Reza Karimi1,3, Göran Tornling 1, Helena Forsslund1, Mikael Mikko1, Åsa M. Wheelock1, Sven Nyrén2,3 and C. Magnus Sköld1,3 Affiliations: 1Dept of Medicine and Centre for Molecular Medicine (CMM) Respiratory Medicine Unit, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. 2Dept of Molecular Medicine and Surgery, Division of Radiology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. 3These authors contributed equally. Correspondence: Reza Karimi, Dept of Medicine Solna, Karolinska Institutet, Lung-Allergy Clinic N2:02, Karolinska University Hospital Solna, SE 171 76 Stockholm, Sweden. E-mail: [email protected] @ERSpublications Smokers with regional air trapping on expiratory CT scan are less obstructive/have less emphysema than those without http://ow.ly/96lV305tgtZ Cite this article as: Karimi R, Tornling G, Forsslund H, et al. Differences in regional air trapping in current smokers with normal spirometry. Eur Respir J 2017; 49: 1600345 [https://doi.org/10.1183/13993003.00345- 2016]. ABSTRACT We investigated regional air trapping on computed tomography in current smokers with normal spirometry. It was hypothesised that presence of regional air trapping may indicate a specific manifestation of smoking-related changes. 40 current smokers, 40 patients with chronic obstructive pulmonary disease (COPD), and 40 healthy never- smokers underwent computed tomography scans. Regional air trapping was assessed on end- expiratory scans and emphysema, micronodules and bronchial wall thickening on inspiratory scans. The ratio of expiratory and inspiratory mean lung attenuation (E/I) was calculated as a measure of static (fixed) air trapping. Regional air trapping was present in 63% of current smokers, in 45% of never smokers and in 8% of COPD patients (p<0.001). Current smokers with and without regional air trapping had E/I ratio of 0.81 and 0.91, respectively (p<0.001). Forced expiratory volume in 1 s (FEV1) was significantly higher and emphysema less frequent in current smokers with regional air trapping. Current smokers with regional air trapping had higher FEV1 and less emphysema on computed tomography. In contrast, current smokers without regional air trapping resembled COPD. Our results highlight heterogeneity among smokers with normal spirometry and may contribute to early detection of smoking related structural changes in the lungs. Received: July 11 2015 | Accepted after revision: Oct 13 2016 Support statement: Supported by the Swedish Heart-Lung Foundation, the King Oscar II Jubilee Foundation, the Mats Kleeberg Foundation, King Gustaf V and Queen Victoria’s Freemasons Foundation, Sandoz A/S, EU FP6 Marie Curie IRF, Swedish Foundation for Strategic Research (SSF), VINNOVA, Karolinska Institutet and through the Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and Karolinska Institutet. Funding information for this article has been deposited with the Open Funder Registry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conflict of interest: None declared. Copyright ©ERS 2017 https://doi.org/10.1183/13993003.00345-2016 Eur Respir J 2017; 49: 1600345 SMOKING | R. KARIMI ET AL. Introduction Repetitive exposure to cigarette smoke causes epithelial damage and an inflammatory response, which gradually leads to structural changes in the airways and lung parenchyma. These structural changes, “remodelling”, are the hallmarks of chronic obstructive pulmonary disease (COPD). It is now generally accepted that the small airways with diameter less than 2 mm are the primary area for early obstruction [1, 2]. Small airways inflammation is considered to precede tissue destruction and development of emphysema [3]. Due to increased branching of the airways and subsequent expansion of the total cross-sectional lumen area, the small airways account for only 10–15% of the total airway resistance [4]. This area is sometimes referred as a “silent zone” because the disease cannot yet be measured by spirometry in an early stage and the patients do not experience significant clinical symptoms until substantial damage to the lungs has occurred [5]. The employment of computed tomography offers opportunity for early evaluation of subclinical, smoking-related pathological changes in the airways and lung parenchyma [6–8]. These early changes, distinguishable on inspiratory computed tomography scans as “tree in bud” and micronodules, gradually progress and lead to detachment of alveolar walls from the respiratory bronchiole to develop centrilobular emphysema [9]. Regional air trapping due to retention of air in the distal part of the respiratory tract appears, on expiratory computed tomography scans, as low attenuation patchy areas, which is regarded as a surrogate for small airways disease [10–12]. Quantification of pulmonary emphysema on computed tomography as volume of voxels below the threshold of –950 Hounsfield units is well established [13, 14]. The ratio of mean lung attenuation on paired expiratory and inspiratory scans has been considered to quantify air trapping and has been proposed as an indicator for small airways disease [15–17]. In COPD and asthma, the ratio has been shown to be increased [18, 19]. However, since the attenuation-based measurements are influenced by both hyperinflation and airways obstruction, visual assessment of regional air trapping on expiratory computed tomography scans may indicate a different finding [10]. This study was undertaken to compare visual assessments of early lungs lesions on computed tomography, with quantitative measurements and to signs of local and systemic inflammation. We hypothesised that a combination of quantitative lung attenuation measurements and visual assessment of morphological abnormality, i.e. regional air trapping on expiratory computed tomography scans and presence of micronodules, emphysema and bronchial wall thickening on inspiratory computed tomography, would reveal early pulmonary changes in smokers with normal spirometry. Furthermore, we performed bronchoscopy with bronchoalveolar lavage in order to characterise the inflammatory response in the distal airways, to reveal a potential link between imaging and smoking induced pathobiology. Materials and methods Subjects The study was conducted as a part of the Karolinska COSMIC (COPD Smoking Proteomic) study, ClinicalTrials.gov identifier NCT02627872, [8, 20, 21]. Briefly, 45–65-year-old healthy never-smokers (n=40), Current smokers (hereafter referred as smokers) with normal spirometry (n=40) and COPD patients, Global Initiative for Chronic Obstructive Lung (GOLD) I and II (n=40) were included. Detailed demographic characteristics of the investigated groups have been published previously [8, 20] and a summary is shown in table 1. Of the COPD patients, 28 were current smokers and 12 were ex-smokers (smoking cessation >2 years). A medical examination and a standard chest radiograph were performed. Subjects with any significant medical condition, including asthma and allergy were not included. Inhaled or oral corticosteroids and exacerbation or airways infection during at least 3 months prior to inclusion were not allowed. Lung function Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured 20 min after bronchodilatation with two inhalations of 0.5 mg terbutalin (Bricanyl Turbuhaler; AstraZeneca, Södertälje, Sweden) using a spirometer (Vmax 229–6200 Legacy, Viasys, Yorba Linda, CA, USA). Total lung capacity and residual volume were measured by body plethysmography. Transfer factor of the lungs for carbon monoxide (TLCO) was measured by the single-breath method. Lung function data, including standardised residuals, i.e. Z-scores are presented in tables 1 and 2. Lower limits of normal (LLN) for FEV1/FVC, FVC and FEV1 were calculated, using GLI-2012 references [22] and the equations of the European Community of Coal and Steel (ECCS) [23] were used calculating static lung volumes and TLCO. All never smokers and smokers with normal spirometry had FEV1/FVC >LLN. Two females and five males with COPD, had FEV1/FVC >LLN. However, the ratio of FEV1/FVC was <0.70 which was the inclusion criteria for the study. The other COPD patients had FEV1/FVC <LLN. https://doi.org/10.1183/13993003.00345-2016 2 SMOKING | R. KARIMI ET AL. TABLE 1 Demographic, lung function, quantitative and morphological computed tomography measurements for never smokers, smokers and COPD patients Never smokers Smokers COPD patients Subjects n 40 40 40 Demographics and lung function Male/female % 50/50 50/50 50/50 Age years 57.0±7.0 54.0±6.2 59.2±5.3+ − Body mass index kg·m 2 25.9±3.7 24.3±3.1 25.3±4.1 Smoking history pack-years NA 35.2±12 38.0±11 Current smoking NA 17.8±7 16.4±6¶ ## §§§,+++ FEV1 % predicted 118±13 109±12 79±12 ### §§§,+++ FEV1 Z-score 0.9 (−1.3–2.5) 0.2 (−1.1–1.9) −1.7 (−3.5–−0.5) §§§,+++ FEV1/FVC 0.82 0.78 0.61 ## §§§,+++ FEV1/FVC Z-score 0.3 (−1.5–2.6) −0.1 (−1.3–1.4) −2.3 (−4,2–−0.8) TLC % predicted 106±10.7 107±11.1 108±14.6 TLC Z-score 0.4 (−1.0–2.3) 0.4± (−1.5–1.7) 0.5 (−1.4–2.4) RV % predicted 102±25 113±23 138±34+++,§§§ RV Z-score 0.1 (1.0–2.6)+++,§§§ 0.8 (−1.4–2.4) 0.8 (−0.7–2.7) ### +++,§§§ TLCO % predicted 91±11 78±12 67±13 +++,### +++,§§§ TLCO Z-score −0.6 (−2.2–1.4) −1.6 (−4.6–0.37) −2.3 (−4.0–0.7) Quantitative computed tomography Mean lung attenuation at expiration HU −776±40 −756±45# −809±39+++,§§§ Mean lung attenuation at inspiration HU −874±20 −857±28###,+++ −876±17 E/I ratio 0.89±0.04 0.88±0.05 0.93±0.05+++,§§§ LA-950 at inspiration 27.4±6.2 21.3±6.6###,+++ 27.6±6.8 Morphological (computed tomography) Emphysema 0 (0) 22 (55)### 32 (80)§§§ Regional air-trapping 18 (45) 25 (63) 3 (8)+++,§§§ Bronchial wall thickening 5 (12) 30 (75)### 32 (80)§§§ Nodules larger than 3 mm 15 (38) 21 (52) 23 (58) Micronodules 0 23 (58)### 15 (38)+,§§§ Data are presented as mean±SD, mean (range) or n (%), unless otherwise stated.